Spencer O Scholz, Alexander S Dudnik, Aristidis Vasilopoulos, Zhaozhong J Jia, Anna Albertson, Brian S Brown, Liye Chen, Renhe Li, Gaoyuan Ma, Longcheng Wang, Akinori Okano, Xianrui Zhao, Xingyu Jiang, Caleb Karmel, Patrick B Brady, Chunqiu Lai, Hemantkumar Deokar, Felix DeAnda, Somdutta Roy, Manasi Mayekar, Hana Choi, Louis Lin, David G Belair, Anand Joshi, Woo Hyun Yoon, Andrea Montano, Xiaoping Xie, Henry Nguyen, Haiyan S Li, Chin Pan, Ben Danna, Deepak Gurbani, Jingzhi Li, Alla Korepanova, Tao Li, Tarikere Gururaja, Rong-Xian Ding, Rinku Jain, Ruth L Martin, Rebecca Kohnken, Alexey Rivkin
Decapping Scavenger (DcpS) enzyme, a pyrophosphatase involved in mRNA regulation via mRNA cap degradation, has been identified as a promising oncology target in fragile histidine triad (FHIT) deficient cancers such as AML and GBM but remains underexplored in broader solid tumor indications. We have discovered a novel DcpS inhibitor, compound 17, which has a differentiated binding mode relative to known inhibitors, engaging the second nucleotide-binding domain of the mRNA cap substrate. Compound 17 possesses superior levels of potency in NSCLC A549 cell line relative to known inhibitors and demonstrates excellent selectivity against DcpS-insensitive cell lines, high levels of bioavailability in preclinical species, and mitigated hERG liabilities. Finally, compound 17 demonstrates oral dose-dependent efficacy in two solid tumor xenograft models, A253 and EBC-1, highlighting the promise of DcpS as a novel target in FHIT low/deficient solid tumors.